Masterclass November 2017

01 Nov 2017

Prof Jeroen Geurts

Cognitive decline in MS: stuck in disease?

Hanneke Hulst, Anand Eijlers, Jeroen Geurts

Cognitive impairment in MS is nowadays recognized as one of the most disabling symptoms of the disease, affecting up to 70% of all patients.1 Deficits vary from patient to patient and can be present in all stages of the disease.2 Problems with information processing speed (‘cognitive slowing’) and memory are most often reported.3,4

In search of the underlying neurobiological mechanisms of cognitive decline in MS, several studies used advanced neuroimaging techniques to demonstrate structural (atrophy, gray matter lesions) and functional (activation, connectivity) changes in specific brain regions (e.g. thalamus, hippocampus, dorsolateral prefrontal cortex) that were strongly associated with cognitive impairment.5-12 Additionally, using these advanced neuroimaging measures cognitively preserved patients could be distinguished from cognitively impaired patients on a group level.13

In 2010, the functional reorganization hypothesis was introduced as an attempt to explain the functional MRI (fMRI) findings during cognitive paradigms in patients with MS.14 Increased activation of task-related brain regions as well as the recruitment of additional brain regions not normally involved in the task at hand were observed in cognitively preserved, but not in cognitively impaired MS patients. These changes were therefore interpreted as compensatory and beneficial, preserving normal cognitive functioning. In cognitively impaired patients this so-called compensatory mechanism was thought to be exhausted, leading to decreased brain activation and overt cognitive deficits. 8-11,13

In the years that followed, new insights were obtained from resting-state (no task) fMRI studies, demonstrating both increases and decreases in functional connectivity between brain regions at rest, which were both related to better cognitive performance.15-17 These findings added an extra level of complexity to the understanding of cognitive impairment in MS and was reason to revise the original hypothesis. The revised hypothesis postulated a decline in network efficiency as a potential underlying substrate of cognitive decline in MS, comprising changes in regional activation or connectivity between brain regions as well as changes in higher order network organization.18

And with the introduction of the revised hypothesis, another problem emerged: ‘how do we measure network efficiency?’ While this is currently still a matter of debate and no gold standard exist for measuring network efficiency, the investigation of brain functioning from a network perspective and especially the evaluation of network dynamics might be a step in the right direction. Different from static connectivity studies, this also takes into account dynamic changes in the way brain regions communicate with each other. An example of such a study was recently presented at the ECTRIMS congress in Paris (24-10-2017, Eijlers et al.) which showed that the position of the default-mode network, a group of brain regions primarily active during rest and involved in introspective processing, within the broader functional network has not only become more central, but also less dynamic in cognitively impaired MS patients during the resting state. This could indicate that the default-mode network is stuck in a highly central state, hampering the normal attenuation of this network during cognitive processing, which might lead to the observed deficits in cognitive functioning.

Understanding cognitive decline in patients with MS is highly complex and involves the interplay between structural brain damage and functional brain changes. A challenge for the near future would be to further increase our understanding of how this interplay evolves and whether rigidity of the network (i.e. being ‘stuck in disease’) is a contributing factor when it comes to cognitive decline in MS.